Fused ring compound, pharmaceutical composition containing same, and use of fused ring compound

Abstract

The present invention relates to the technical field of medicines, and provides a fused ring compound, a pharmaceutical composition containing the same, and use of the fused ring compound. The compound has a structure as shown in formula (I), or a tautomer, a mesomer, a racemat, an enantiomer, a diastereoisomer or a mixture thereof, a metabolite, a metabolic precursor, an isotope substitution form, a pharmaceutically acceptable salt, a hydrate, a solvate, a polymorph or a cocrystal thereof. The compound provided by the present invention can be used for treating cancers caused by KRAS mutation. The cancers caused by KRAS mutation are selected from one or more cancers caused by KRAS G12C, KRAS G12V, KRAS G12A and G12D mutations. In particular, the compound can serve as a G12D inhibitor and has relatively high inhibitory activity.

1 . A compound represented by formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         A 1 , A 2 , A 3 , A 4 , A 5  and A 6  are each independently selected from the group consisting of C—R 4  and N, 
         R 1  is selected from the group consisting of substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, 
         R 2  is selected from the group consisting of substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl, 
         R 3  is selected from the group consisting of substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl, 
         R 4  in A 1 , A 2 , A 3 , A 4 , A 5  and A 6  is independently selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, substituted or unsubstituted unsaturated cyclyl or heterocyclyl, substituted or unsubstituted aryl or heteroaryl, hydroxy, cyano, amino, ester, nitro, thiol, amido, sulfonyl, phosphoryl, alkylphosphinoyl, alkylsulfonyl and alkylsulfinyl; 
         L 1  and L 2  are absent or independently selected from the group consisting of —CH═CH—, —N(Ra)—, —N(Ra)—(CRaRb)n-, —O—(CRaRb)n-, and —(CRaRb)n-; 
         Ra and Rb are each independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, and C 3 -C 6  cycloalkyl. 
       
     
     
         2 . The compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 1 , having a structure represented by formula (II), 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is selected from the group consisting of substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, 
         R 2  is selected from the group consisting of substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl, 
         R 3  is selected from the group consisting of substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl, 
         L 1  is absent or selected from the group consisting of —N(Ra)— and —N(Ra)—(CRaRb)n-, L 2  is selected from the group consisting of —O—(CRaRb)n-, —CH═CH—, and —(CRaRb)n-, and Ra and Rb are each independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, and C 3 -C 6  cycloalkyl. 
       
     
     
         3 . The compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 2 , having a structure represented by formula (III) or (IV), 
       
         
           
           
               
               
           
         
         wherein, 
         ring A is a 4- to 12-membered heterocyclic ring with N and/or O as a heteroatom; 
         ring B is a 4 to 12-membered heterocyclic ring with N as a heteroatom, the ring A and ring B are ach independently selected from the group consisting of a saturated or partially saturated monocycle, fused ring, bridged ring, and spiro ring, 
         Z is selected from the group consisting of hydrogen and deuterium; 
         R 1  is selected from the group consisting of substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, 
         R 5 , R 6 , and R 7  are each independently selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonate, and phosphate, wherein the substituent is each independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonate, and phosphate, 
         m1 is an integer of 0 to 6; and 
         m2 is an integer of 0 to 6. 
       
     
     
         4 . The compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 3 , wherein ring B is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein, 
         X 1  and X 2  are independently selected from the group consisting of hydrogen, deuterium, and halogen; Y is selected from the group consisting of hydrogen and deuterium; 
         R 8 , R 20 , and R 21  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted alkyl or cycloalkyl, and substituted or unsubstituted heteroalkyl or heterocycloalkyl; 
         R 9 , R 10 , and R 22  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, ester, amido, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphonyl, sulfonate, and phosphate, wherein the substituent is each independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphonyl, sulfonate, and phosphate; and 
         R 11  is substituted monocyclic heteroalkyl with nitrogen and/or oxygen as a heteroatom. 
       
     
     
         5 . The compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 3 , wherein ring A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         ring C is 
       
       
         
           
           
               
               
           
         
         wherein, 
         X 3  to X 16  are each independently selected from the group consisting of NR 12 —, —O—, —CO—, and —CR 14 R 15 —; 
         R 12 , R 14 , and R 15  are each independently selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonate, and phosphate, wherein the substituent is each independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonate, and phosphate; and 
         q is an integer of 0 to 3, and q=0 indicates this chemical bond is absent. 
       
     
     
         6 . The compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 3 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein, W 1 , W 3 , W 5 , W 8 , W 9 , W 11 , W 12 , W 13 , W 15 , W 16 , and W 17  are each independently selected from the group consisting of —NR 12 —, —O—, —CO—, —CR 17 R 18 —, and —SO 2 —; W 2 , W 4 , W 6 , W 7 , W 10 , W 14 , W 18 , W 19 , W 20 , W 21 , W 22 , W 23 , W 24 , W 25 , W 26 , and W 27  are each independently selected from the group consisting of N atom, and C atom with R 16  as a substituent; when W 23  and W 24  are C atoms with R 16  as a substituent, the two carbon atoms are optionally connected by a chemical bond to form a saturated or unsaturated 5-membered or 6-membered ring; and 
         R 12 , R 16 , R 17 , and R 18  are each independently selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, hydroxy, alkynyl, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonate, and phosphate, wherein the substituent is each independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidino, sulfonyl, phosphoryl, sulfonate, and phosphate. 
       
     
     
         7 . The compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 3 , having a structure represented by formula (V), formula (VI) or formula (VII): 
       
         
           
           
               
               
           
         
         wherein, 
         X 1  and X 2  are independently selected from the group consisting of hydrogen, deuterium, and halogen; Y is selected from the group consisting of hydrogen and deuterium; Z is selected from the group consisting of hydrogen and deuterium; 
         R 8 , R 20 , and R 21  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted alkyl or cycloalkyl, and substituted or unsubstituted heteroalkyl or heterocycloalkyl; 
         R 22  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, ester, amido, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphonyl, sulfonate, and phosphate, wherein the substituent is each independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphonyl, sulfonate, and phosphate; 
         X 3  is selected from the group consisting of —NR 12 —, —O—, —CO—, and —CR 14 R 15 —; and 
         W 19 , W 20 , and W 22  are independently selected from the group consisting of N atom, and C atom with R 16  as a substituent. 
       
     
     
         8 . The compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 7 , having a structure represented by formula (VIII), formula (IX) or formula (X): 
       
         
           
           
               
               
           
         
         wherein, X 1  and X 2  are independently selected from the group consisting of hydrogen, deuterium, and halogen; Y is selected from the group consisting of hydrogen and deuterium; Z is selected from the group consisting of hydrogen and deuterium; 
         X 3  is selected from the group consisting of —NR 12 —, —O—, —CO—, and —CR 14 R 15 —; 
         W 19 , W 20 , and W 22  are each independently selected from the group consisting of N atom, and C atom with R 16  as a substituent; 
         R 19  is selected from the group consisting of —H, —OH, halogen, —NO 2 , —CN, —CF 3 , —C 2 F 5 , —OCF 3 , —OCHF 2 , —OCH 2 F, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, alkoxy, alkynyl, ester, amido, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphonyl, sulfonate, and phosphate, wherein the substituent is each independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphonyl, sulfonate, and phosphate; 
         R 22  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, alkoxy, alkynyl, ester, amido, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphonyl, sulfonate, and phosphate, wherein the substituent is each independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, acylguanidinyl, sulfonyl, phosphonyl, sulfonate, and phosphate; and 
         m3 is an integer of 0 to 5, and when m3 is greater than or equal to 2, R 19  is optionally a 4- to 7-membered ring connected in parallel with a benzene ring. 
       
     
     
         9 . The compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 3 , having a structure represented by formula (XI) or formula (XII): 
       
         
           
           
               
               
           
         
         wherein Y is selected from the group consisting of hydrogen and deuterium; Z is selected from the group consisting of hydrogen and deuterium; 
         wherein R 23  in formula (XI) is independently selected from the group consisting of —H, —F, —Cl, —CN, —CF 3 , alkenyl, alkynyl, C 1-3  linear alkyl, and C 3-6  cycloalkyl; 
         R 24  is selected from the group consisting of —H, C 1-5  alkyl or heteroalkyl, and —COR 55 , and R 55  is selected from the group consisting of —H, C 1-10  linear/branched alkyl, C 1-10  linear/branched heteroalkyl, C 3-6  cycloalkyl, and C 3-6  heterocycloalkyl; 
         R 25  is selected from the group consisting of —H, —CO(C 0-10  alkyl), —COO(C 0-10  alkyl), —COO—CH 2 —OCO(C 0-10  alkyl), and —COO—CH(CH 3 )—OCO(C 0-10  alkyl); 
         K is selected from the group consisting of C and N, when K is N, R 29  is absent; 
         R 26 , R 27 , R 28 , R 29  and R 30  are each independently selected from the group consisting of —H, —OH, halogen, —NO 2 , —CN, —CF 3 , —C 2 F 5 , —OCF 3 , —OCHF 2 , —OCH 2 F, phosphate, monomethylphosphate, dimethylphosphate, C 1-5  linear/branched alkyl, C 1-5  alkoxy, C 3-10  cycloalkyl, C 3-10  heterocycloalkyl, —N(C 0-10  alkyl)(C 0-10  alkyl), —S(C 0-10  alkyl), —OCON(C 0-10  alkyl)(C 0-10  alkyl), C 5-6  aryl, five-membered heteroaryl, and six-membered heteroaryl; alternatively, R 27 , R 28  and the carbon atom between R 27  and R 28  form saturated or unsaturated C 3-8  cycloalkyl, saturated or unsaturated C 3-8  heterocycloalkyl, saturated or unsaturated cyclic lactone, C 5-6  aryl, bridged cycloalkyl, or spirocycloalkyl, wherein H thereof is optionally substituted with —D, —OH, —F, —NO 2 , —CN, —CF 3 , —C 2 F 5 , C 1-3  alkyl, or amido; 
         m4 is an integer of 0 to 4; 
         wherein, R 31  in formula (XII) is independently selected from the group consisting of —F, —Cl, —NH 2 , —CN, —CF 3 , —C 2 F 5 , —OCF 3 , alkenyl, alkynyl, C 1-3  linear/branched alkyl, C 1-3  linear/branched alkoxy, C 3-6  cycloalkyl, aryl, and heteroaryl; 
         R 32  is selected from the group consisting of —H, C 1-5  linear/branched alkyl, and C 3-6  cycloalkyl; 
         R 33  is selected from the group consisting of —H, —CO(C 0-10  alkyl), —COO(C 0-10  alkyl), —COO—CH 2 —OCO(C 0-10  alkyl), and —COO—CH(CH 3 )—OCO(C 0-10  alkyl); 
         R 34 , R 35 , R 36 , R 37 , and R 38  are independently selected from the group consisting of —H, —OH, halogen, —NO 2 , —CN, —CF 3 , —C 2 F 5 , —OCF 3 , —OCHF 2 , —OCH 2 F, C 1-5  linear/branched alkyl, C 1-5  alkoxy, C 3-10  cycloalkyl, and C 3-10  heterocycloalkyl; alternatively, R 35 , R 36  and the carbon atom between R 35  and R 36  form saturated or unsaturated C 3-8  cycloalkyl or saturated or unsaturated C 3-8  heterocycloalkyl, wherein H thereof is optionally substituted with —D, —OH, —F, —NO 2 , —CN, —CF 3 , —C 2 F 5 , C 1-3  alkyl, or amido; and 
         m5 is an integer of 0 to 4. 
       
     
     
         10 . The compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 9 , having a structure represented by formula (XIII) or formula (XIV): 
       
         
           
           
               
               
           
         
         wherein, R 39  and R 40  are independently selected from the group consisting of —H, —F, —Cl, —CN, alkynyl, and C 1-3  linear alkyl; R 41 , R 42 , R 43 , and R 44  are independently selected from the group consisting of —H, —OH, —F, —Cl, —CN, —CF 3 , —C 2 F 5 , —OCF 3 , monomethylphosphoryl, dimethylphosphoryl, C 1-5  linear/branched alkyl, C 1-5  alkoxy, C 3-10  cycloalkyl, C 3-10  heterocycloalkyl, —S(C 0-10  alkyl), —OCON(C 0-10  alkyl)(C 0-10  alkyl), C 5-6  aryl, five-membered heteroaryl, and six-membered heteroaryl; alternatively, R 42 , R 43  and the carbon atom between R 42  and R 43  form saturated or unsaturated C 3-8  cycloalkyl, saturated or unsaturated C 3-8  heterocycloalkyl, five-membered cyclic lactone, C 5-6  aryl, bridged cycloalkyl, or spirocycloalkyl, wherein H thereof is optionally substituted with —D, —OH, —F, —NO 2 , —CN, —CF 3 , —C 2 F 5 , C 1-3  alkyl, or amido; and 
         R 45  and R 46  are independently selected from the group consisting of —H, —F, —Cl, —NH 2 , —CN, —CF 3 , —C 2 F 5 , —OCF 3 , alkynyl, C 1-3  linear alkyl, C 1-3  alkoxy, C 3-6  cycloalkyl, aryl, and heteroaryl; R 47 , R 48 , and R 49  are independently selected from the group consisting of —H, —F, —Cl, —CN, —CF 3 , and —C 2 F 5 ; alternatively, R 47 , R 48  and the carbon atom between R 47  and R 48  form saturated or unsaturated C 3-8  cycloalkyl or saturated or unsaturated C 3-8  heterocycloalkyl, wherein H thereof is optionally substituted with —D, —OH, —F, —CN, —CF 3 , or C 1-3  alkyl. 
       
     
     
         11 . The compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 10 , wherein R 42 , R 43  and the carbon atom between R 42  and R 43  on the benzene ring in formula (XIII) form saturated or unsaturated C 3-8  cycloalkyl, saturated or unsaturated C 3-8  heterocycloalkyl, five-membered cyclic lactone, C 5-6  aryl, bridged cycloalkyl, or spirocycloalkyl, selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein, K 2 , K 3 , and K 4  are fused with the benzene ring to form a saturated or unsaturated five-membered ring, K 2 , K 3 , and K 4  are independently selected from the group consisting of C, N, O, and S; K 5 , K 6 , and K 7  are independently selected from the group consisting of C, N, O, and S; K 8  is independently selected from the group consisting of C, N, O, and S; R 50 , R 51 , R 52 , and R 53  are independently selected from the group consisting of —H, —D, —OH, —F, —NO 2 , —CN, —CF 3 , —C 2 F 5 , C 1-3  alkyl, C 1-3  alkoxy, and C 3-6  cycloalkyl; m6, m7, m8, and m9 are each an integer of 0 to 6; 
         R 47 , R 48  and the carbon atom between R 47  and R 48  on the benzene ring in formula (XIV) form saturated or unsaturated C 3-8  cycloalkyl or saturated or unsaturated C 3-8  heterocycloalkyl, selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         K 9 , K 10 , and Ku are independently selected from the group consisting of C, N, and O; R 54  is independently selected from the group consisting of —H, —F, —CN, —CF 3 , —C 2 F 5 , C 1-3  alkyl, C 1-3  alkoxy, and C 3-6  cycloalkyl; and m10 is an integer of 0 to 4. 
       
     
     
         12 . The compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 1 , wherein the structure represented by formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition comprising an active compound selected from the group consisting of the compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 1 , and a combination thereof. 
     
     
         14 . A method for inhibiting KRAS in a host cell, comprising contacting the host cell with the compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 1 . 
     
     
         15 . A method for treating, alleviating or preventing a disease or condition, comprising administering to a subject in need thereof the compound, or the tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, metabolite, metabolic precursor, isotope-substituted form, pharmaceutically acceptable salt, hydrate, solvate, polymorph or cocrystal thereof according to  claim 1 , wherein the disease or condition is associated with Noonan syndrome, LEOPARD syndrome, leukaemia, neuroblastoma, melanoma, oesophageal cancer, head and neck tumors, breast cancer, lung cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, colorectal and colon cancer. 
     
     
         16 . The method according to  claim 14 , wherein the KRAS is KRAS G12D mutant.